This proposal describes a 5-year training program for the development of an academic career in Patient-Oriented Research. Kai I. Cheang, Pharm. D., seeks support for this research training in order to establish herself as an independent clinical investigator in insulin resistance in women's health. John E. Nestler, M.D. will mentor the principal investigator's scientific development. Dr. Nestler is a recognized leader in the field of insulin resistance in the polycystic ovary syndrome (PCOS). In addition, an advisory committee of highly regarded scientists and statistician will provide scientific and career advice. The candidate's institution provides an excellent environment for interdisciplinary research, and will commit at least 75% of Dr. Cheang's efforts to her research and training activities for this award. Research will focus on the role of a putative inositol phosphoglycan (IPG) mediator of insulin action in PCOS. Previous studies of the applicant's mentor demonstrated that a deficiency in D-chiro-inositol (DCI) containing IPG, accompanied by an increase in DCI renal clearance, may contribute to insulin resistance in PCOS. However, increased DCI renal clearance was only evident in obese women with PCOS, but not in obese normal women, or in non-obese PCOS or normal women. Coincidentally, obesity was associated with a 5-fold reduction in insulin sensitivity in PCOS women, but only a 2-fold reduction in the normal women. Since insulin sensitivity is inversely correlated with DCI renal clearance, we propose that the difference in DCI renal clearance between obese PCOS and normal women could partially explain the disproportionate reduction in insulin sensitivity in obese PCOS women compared to obese normal women. Our hypothesis is that obesity modulates the renal clearance of DCI in women with PCOS, but not in normal women. We further propose that increased DCI renal clearance leads to a reduction in DCI availability and aggravates insulin resistance in women with PCOS. The specific aims include: (1) Determine if DCI renal clearance in obese women with PCOS is increased compared to age- and weight-matched, obese normal women; (2) Determine if weight loss reduces DCI renal clearance in obese women with PCOS, but not in age- and weight-matched obese normal women; (3) Determine if a change (reduction) in DCI renal clearance as a result of weight loss is correlated with a change (improvement) in insulin sensitivity in obese women with PCOS that is independent of weight loss itself; and (4) Determine if an equivalent degree of weight loss in obese women with and without PCOS is associated with (i) a greater reduction in DCI renal clearance, and (ii) a greater improvement in insulin sensitivity in the PCOS women compared to the normal women. Relevance: PCOS is a major cause of female infertility. Insulin resistance plays an important role in the disorder. The research proposed is significant, because it will advance the understanding of the nature of the insulin resistance in PCOS and provide insights into new treatment strategies. [unreadable] [unreadable] [unreadable]